Author’s Accepted Manuscript image

Use of a gabapentin protocol for the management of

alcohol withdrawal: a preliminary experience
expanding from the consultation/liaison psychiatry
serviceA gabapentin protocol for alcohol withdrawal☆

Jonathan G. Leung, Daniela Rakocevic, Nicholas D.

Allen, Elliot M. Handler, Bruno A. Perossa, Kristin L.
Borreggine, Amy L. Stark, Hannah K. Betcher, Daniel www.elsevier.com/locate/bios
K. Hosker, Blaine A. Minton, Benjamin R. Braus, Ross
A. Dierkhising, Kemuel L. Philbrick

PII: S0033-3182(18)30138-5
DOI: https://doi.org/10.1016/j.psym.2018.03.002
Reference: PSYM864
To appear in: Psychosomatics
Received date: 18 April 2017
Revised date: 17 March 2018
Accepted date: 19 March 2018
Cite this article as: Jonathan G. Leung, Daniela Rakocevic, Nicholas D. Allen,
Elliot M. Handler, Bruno A. Perossa, Kristin L. Borreggine, Amy L. Stark,
Hannah K. Betcher, Daniel K. Hosker, Blaine A. Minton, Benjamin R. Braus,
Ross A. Dierkhising and Kemuel L. Philbrick, Use of a gabapentin protocol for
the management of alcohol withdrawal: a preliminary experience expanding
from the consultation/liaison psychiatry serviceA gabapentin protocol for
alcohol withdrawal☆, Psychosomatics,doi:10.1016/j.psym.2018.03.002
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Title: Use of a gabapentin protocol for the management of alcohol withdrawal: a

preliminary experience expanding from the consultation/liaison psychiatry service

Running title: A gabapentin protocol for alcohol withdrawal

Author information: Jonathan G. Leung, Pharm.D.1; Daniela Rakocevic, M.D. 1;

Nicholas D. Allen, M.D. 1; Elliot M. Handler, M.D. 1; Bruno A. Perossa, M.D. 1; Kristin

L. Borreggine, D.O. 1; Amy L. Stark, M.D. 1; Hannah K. Betcher, M.D. 1; Daniel K.

Hosker, M.D. 1; Blaine A. Minton, D.O. 1; Benjamin R. Braus, M.D.1; Ross A.

Dierkhising, M.S.2, Kemuel L. Philbrick, M.D. 1

1) Mayo Clinic, Rochester, 1216 2nd St SW, Rochester, MN 55902. Department of

Psychiatry and Psychology. 2) Mayo Clinic, Rochester, MN 205 3rd Ave SW 55902.

Division of Biomedical Statistics and Informatics, Department of Health Sciences

Research

Corresponding Author: Jonathan G. Leung, Pharm.D, leung.jonathan@mayo.edu

Financial disclosure: This research did not receive any specific grant from funding

agencies in the public, commercial, or not-for-profit sectors. The authors of this paper

have no sources of financial support or conflicts of interest relevant to this manuscript.

Additional disclosure: Preliminary findings related to this manuscript have been

submitted to the 66th Annual Meeting, Academy of Psychosomatic Medicine as an oral

poster.
 Abstract

Introduction: Benzodiazepines are the conventional mainstay to manage alcohol

withdrawal; however, patients are subsequently at increased risk for poor sleep, cravings,

and return to drinking. Research on alternative pharmacologic agents to facilitate safe

alcohol withdrawal is scant. Gabapentin is one medication shown in small studies to

reduce the need for benzodiazepines in the setting of alcohol withdrawal. The

continuation of gabapentin after alcohol withdrawal appears to be safe during early

sobriety and may aid in reducing alcohol-related cravings or returning to alcohol

consumption. Use of a gabapentin-based, benzodiazepine-sparing protocol began in early

2015 by the Mayo Clinic, Rochester, consultation/liaison psychiatry service. Methods:

A retrospective chart review was conducted to detect any safety concerns with use of a

gabapentin protocol for alcohol withdrawal syndrome. Secondary outcomes were

derived by comparing a matched cohort of patients who received benzodiazepines for

alcohol withdrawal syndrome. Results: Seventy-seven patients received management of

alcohol withdrawal syndrome via a gabapentin protocol during the study period. No

patients required transfer to a higher level of care or had a documented withdrawal

seizure. Length of stay between the gabapentin protocol group and benzodiazepine group

were similar. Conclusion: This preliminary data has supported the frequent utilization of

this protocol in the general internal medicine practice and formalization of an institutional

order set of this protocol for mild to moderate alcohol withdrawal syndrome. Prospective

studies are required to validate findings.

Keywords: gabapentin, alcohol, craving, dependence, withdrawal, alcohol withdrawal

syndrome
 Introduction

It is estimated that up to 50% of alcohol dependent patients will experience

alcohol withdrawal syndrome (AWS) with reduced use.(1) Serious complications of

AWS are often predicted by patient history, comorbidities, and demographic factors.

Serious complications such as seizures or delirium tremens can occur in up to 5% of

patients with AWS. While mortality from AWS has significantly decreased due to

improved recognition and treatment, lethal potential remains. The gold standard for

AWS management in the United States typically involves the use of benzodiazepines. (2)

Over several decades, a symptom-triggered approach for administering benzodiazepines

for uncomplicated AWS has been favored over a scheduled or front-loading regimen. A

symptom-triggered approach has been shown to reduce the quantity and duration of

benzodiazepine administration during hospitalization for AWS. (3, 4) However, this

approach does have limitations. The symptom-triggered approach that commonly uses

the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)

requires patients to be able to communicate given the majority of scale assessment items

involve subjective patient responses. (5) In medically ill patients, many scale items such

as nausea, headache, visual disturbances, diaphoresis, anxiety, or agitation may not be not

specifically related to AWS (e.g., infection, delirium). Further limitations of CIWA-Ar

include patients who embellish their report of withdrawal symptoms and the rater’s

subjective assessment of symptoms. Overall these limitations may result in the under

treatment of AWS or the unnecessary administration of benzodiazepines. (6) When

benzodiazepines are given at high doses or extended durations, drug-induced delirium or

over-sedation can prolong hospitalization or require a need for management in a critical

care setting. (7) Also, the abrupt withdrawal of benzodiazepines that often occurs upon

patient discharge is associated with rebound insomnia, cravings, and potential return to

drinking.(8)

Agents with varying degrees of evidence including phenobarbital, baclofen,

carbamazepine, clonidine, dexmedetomidine, and valproate have been investigated as

either benzodiazepine-sparing or replacement agents in the management of AWS.(9, 10)

However, clinical studies are either limited, of poor design quality, or have small sample

sizes. Thus benzodiazepines continue to be the primary modality used for AWS in the

United States. Gabapentin is an additional medication that has been shown to be

effective in reducing the severity of mild to moderate alcohol withdrawal in limited,

small randomized, controlled trials. Despite a lack of evidence to clearly define the

optimal dosing, optimal duration, and ensure no safety issues, the use of a

benzodiazepine-sparing protocol with gabapentin has previously been reported to result

in the avoidance of benzodiazepines in non-critically ill patients. (11-13)

In early 2015, at Mayo Clinic, Rochester, use of a fixed-dose gabapentin regimen

for the management of AWS began as an informal protocol that was recommended by the

psychiatry consultation service. This protocol was adapted based on previous studies and

information now highlighted in a recent publication on benzodiazepine-sparing strategies

for AWS.(13) The protocol provided scheduled gabapentin with or without adjunctive

valproate, as needed clonidine to target autonomic hyperactivity, and an as needed

antipsychotic to target agitation, delirium, or psychosis. Protocols targeting AWS in

these three domains, often referred to symptom cluster A (central nervous system

excitation), B (adrenergic hyperactivity), and C (delirium) have been previously

described in the literature.(14, 15) This informal protocol initially utilized a 1200 mg

loading dose followed by 800 mg three times daily for four days, 600 mg three times

daily for 2 days, 300 mg three times daily for 2 days before discontinuation of

gabapentin. Gabapentin was recommended to be continued at 600 mg three times daily

for patients wishing to abstain from alcohol provided the patient was proceeding to

participate in a structured chemical dependency treatment program. This was based on

the recent findings from Mason and colleagues.(16) Adjunctive options included

valproate, melatonin, and transdermal clonidine. Through computerized physician order

entry (CPOE), CIWA-Ar protocol was recommended to be discontinued to eliminate

concomitant benzodiazepine use.

This protocol was initially only implemented when recommended by the

psychiatry consultation service but use increased by other non-psychiatric inpatient

service groups. It was quickly noted that multiple variations of the protocol were being

used and there was confusion regarding when benzodiazepines administration or CIWA-

Ar scoring should be continued or halted. In collaboration with psychiatry, internal

medicine, nursing, and pharmacy, the protocol was revised and the following issues were

addressed: 1) Use of the protocol was to be triggered by a Prediction of Alcohol

Withdrawal Severity Scale (PAWSS) score of greater than three which indicates high risk

for moderate to severe AWS. (17) 2) Due to saturable absorption at high doses, a

gabapentin loading dose of 1200 mg was eliminated and the protocol was modified to

start at 900 mg three times daily. A reduced dosing option was made available for those

with an estimated creatinine clearance 30 to 60 mL/minute; and not to be recommended

for those with an estimated creatinine clearance of less than 30 mL/minute. 3) Clonidine
was changed to an oral dosage form because initial application of the transdermal

formulation has an onset of action of 48 to 72 hours. 4) Clinicians may consider

adjunctive valproate for patients with history of severe withdrawal, prior brain injury,

existing seizure disorder, or history of withdrawal seizure. There are no data to support

the use of valproate specifically for patients with these past histories. However, there is

limited data assessing AWS-related seizure rate with use of valproate. One study

previously suggested that the ability to rapidly obtain therapeutic valproate serum

concentrations make it suitable for prevention of AWS-related seizures relative to

carbamazepine which also was associated with greater drug-related side effects.(13, 18)

Additionally, the rationale to keep valproate in the protocol hinged more on the fact there

is data lacking for gabapentin in the prevention of AWS-related seizures. In an effort to

improve the safety and tolerability of valproate, the protocol was to specifically state

patients with hepatic disease or significant hepatic dysfunction should not be given

valproate. Also patients less than 50 kg are not to be placed on the protocol. 5) CIWA-

Ar scoring would continue via the CPOE order set to allow for ongoing nursing

monitoring and to have a standardized threshold for when the primary service would be

notified of clinical changes. The usual vitamin supplementation as a part of the original

CIWA-Ar protocol would continue but all benzodiazepines would be discontinued.

These adaptations, crafted within a multidisciplinary group, allowed for the creation (July

2015) of the protocol that is currently being used at our institution (Figure 1). We

conducted a retrospective chart review to assess how the gabapentin protocol was being

used at our institution with the primary goal to evaluate the safety of this strategy.
 Methods

This IRB approved, single center, retrospective, chart review was conducted at

Mayo Clinic, Rochester, Minnesota. Mayo Clinic, Rochester, is a large integrated

tertiary care academic medical center with 2 hospital campuses totaling over 2,000 beds.

Using an electronic medical record database, patients with an ICD-9 code for alcohol

withdrawal, alcohol withdrawal delirium, or alcohol intoxication from January 1, 2015

until March 1, 2016 were identified, noting gabapentin dosing changed slightly in July

2015. These records were cross-referenced with inpatient pharmacy dispensing records

to identify patients over the age of 18 who were admitted to a medical or surgical unit for

alcohol-related reasons and received gabapentin. Medical records were then manually

evaluated to confirm that gabapentin was ordered during the admission for the purpose of

alcohol withdrawal.

Subjects were excluded if they were: 1) prescribed gabapentin prior to admission;

2) directly admitted to a critical care setting; 3) transferred to a critical care setting and

then gabapentin was initiated after the transfer; 4) admitted for drug overdose; and 5)

patients who had denied access to medical records for research purposes. Also, because

the protocol had not been formalized in early 2015, there was less standardization and

knowledge of gabapentin utilization across the hospital and CIWA-Ar score contingent

benzodiazepines often unintentionally remained ordered and administered. In order to

avoid confounding and optimize assessments, patients were excluded if they received

benzodiazepines in the subsequent days following the initiation of gabapentin (although

the total count of patients excluded for this reason was collected). Benzodiazepines were

permitted to be administered in the emergency department or following admission but

before the initiation of the gabapentin protocol. The total daily dose and duration of

benzodiazepine use in this manner was collected. If a patient had multiple admissions for

AWS that utilized gabapentin for management, only the first encounter was collected

(i.e., patients could only be included once).

In addition to demographic data, Charlson Comorbidity Index scores were

obtained electronically, liver and kidney function laboratory results were collected, and

the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) scores were

retrospectively calculated based on information from the electronic medical record.

Other information gathered from the medical records included maximal daily CIWA-Ar

scale scores, percent of patients requiring a higher level of care (i.e., ICU), and percent of

patients experiencing a seizure following initiation of the gabapentin protocol. Drug

information collected included total daily gabapentin dosing, the use of benzodiazepines

received prior to initiation of gabapentin, and the dosage of adjunctive agents

(antipsychotic, clonidine, or valproate), if utilized.

The primary goal of the retrospective chart review was to describe the percent of

patients who successfully completed (i.e., without ICU transfer or seizure after protocol

initiation) a gabapentin taper for alcohol withdrawal or were deemed medically safe for

discharge prior to completion of a gabapentin taper.

Secondary outcomes were to compare the gabapentin protocol group to patients

admitted to a medical or surgical unit for alcohol-related reasons on benzodiazepines for

AWS management. Patients in the second group were identified by ICD-9 codes for

alcohol withdrawal, alcohol withdrawal delirium, or alcohol intoxication from January 1,

2015 until March 1, 2016 and were ordered a CIWA-Ar protocol. The same
demographic information, laboratory results, CCI scores, and PAWSS related data were

collected as the gabapentin protocol group. Patients in the benzodiazepine group were

permitted to be prescribed gabapentin as long as it was not initiated for the purpose of

managing AWS. If a patient was prescribed gabapentin, the indication and dose were

documented. The gabapentin protocol group and benzodiazepine group were matched

based on age (+ 4 years) and sex. Using a paired t-test, length of stay and maximum

daily CIWA-Ar scores over the first three days of treatment were compared between

groups. Given a matched set of 77 patients there would be 80% power with a type I error

of 0.05 to detect a mean length of stay difference of approximately 1-1.2 days (assuming

a standard deviation of 2.7 and a correlation of 0.3 or less)(19) or CIWA-Ar score

difference of 1.5-2.7 (assuming a standard deviation of 3.9-5.8 and a correlation of 0.3 or

less).(20) Finally, McNemar’s test was used to compare the percentage of patients who

had a CIWA-Ar score greater than 8 in the first three days of treatment between groups.

Results

During the assessed time period 93 patients met the inclusion criteria of having a

hospital admission related to alcohol and received gabapentin at any time for the sole

purpose of managing AWS. Five patients were excluded as they were directly admitted

to the ICU. An additional three patients were transferred to the ICU after being admitted

to a general medical service. However, in each of these cases gabapentin was initiated

after the transfer to the ICU. Eight patients were excluded from the gabapentin cohort

having received CIWA-Ar contingent benzodiazepines in addition to the gabapentin

protocol. In reviewing these cases, only one of the eight patients had the gabapentin
protocol ordered prior to CIWA-Ar contingent benzodiazepines. This patient received 2

mg, 3 mg, and 1 mg lorazepam equivalents on hospital days 2, 3, and 4, respectively.

Subsequently, 77 patients were included in the primary assessment of the

gabapentin protocol. The mean age of these patients was 48.7 + 11.4 years of which 56

(72.7%) were male. The mean PAWSS scale for these patients was 4.7 + 1.4 with 62

(80.5%) of patients having a PAWSS score of at least 4 indicating a high risk for

complicated withdrawal. In this gabapentin protocol group 51.9% of patients received a

mean of 2.3 + 1.6 mg of lorazepam equivalents in the emergency department. Diazepam,

which has a long half-life, and could more likely impact AWS in subsequent days, was

administered in the emergency department to 4 patients in doses ranging from 10-20 mg.

Patient characteristics are summarized in Table 1.

In the gabapentin protocol group, no patients were transferred to a critical care

setting. While there were three noted or possible seizures either in the field or emergency

department, these occurred prior to the initiation of the gabapentin protocol. The mean

first CIWA-Ar score of admission for these patients was 8.5 + 6.3. (n=2 had no CIWA

scores during hospitalization). In this group, patients who received lorazepam

equivalents prior to the initiation of a gabapentin protocol on hospital day 1 (n=32) and

day 2 (n=15), received an average of 4.7 + 5.0 mg and 10.8 ± 15.0 mg, respectively.

None of these patients received any benzodiazepines in subsequent days, all having been

switched to the gabapentin protocol. Gabapentin was initiated within the first 24 hours of

admission in 47 (61%) patients and in 73 (94.8%) patients within the first 2 days of

admission. Psychiatric consultation specifically recommended use of the gabapentin for

49 (63.6%) of the patients with the remaining patients ordered the gabapentin protocol at
the initiative of the primary medical service. Fifty-nine (76.6%) patients were discharged

with a prescription for gabapentin of which 47 (61%) were intended tapers and the

remaining prescriptions were continued for the promotion of sobriety.

When the gabapentin protocol group was matched to a second benzodiazepine

group, no difference in the average length of stay was found (gabapentin protocol 5.2

days vs benzodiazepine 5.03 days, p= 0.86). The gabapentin protocol group included one

patient who had an 84 day hospitalization. This one patient was noted to be clinically

stable on day 7 of the hospital admission but remained in the hospital due to a civil

commitment and was waiting for psychiatric placement. After excluding the matched

pair with this patient from the analysis there was still no difference in average length of

stay (gabapentin protocol 4.2 days vs benzodiazepine 5.07 days, p=0.11). There was a

statistically significant difference between groups on day 2 and day 3 of treatment with

regards to CIWA-Ar daily maximum scores as well as the percent of patients who had a

maximum daily CIWA-Ar score of greater than eight (Figure 2 and 3). Adjunctive

clonidine, antipsychotics, or valproate were initiated in 8 (10.4%), 9 (11.7%), and 28

(36.4%) patients, respectively, for the management of AWS in the gabapentin protocol

group. In the benzodiazepine group, adjunctive clonidine, antipsychotics, or valproate

were initiated in 3 (3.9%), 4 (5.2%), and 1 (1.3%) patients, respectively. Data related to

CIWA-Ar scores and medication administered for the first six days of hospitalization is

presented in Table 2.
 Discussion

Gabapentin is an antiepileptic drug that is currently utilized for a variety of FDA

approved and off-label indications.(21) In AWS, gabapentin may enhance GABA

activity by increasing GABA concentrations via interaction with α2δ subunit of voltage-

dependent calcium channels and by direct synthesis.(22) These possible mechanisms

have translated to the successful use of gabapentin for AWS in a limited number of small,

well-conducted studies.(11, 23, 24) Yet, it is important to note that gabapentin does not

interact with GABAA receptors, the mechanism of benzodiazepines. This is a possible

limitation for the safe use of gabapentin in severe AWS as monotherapy. Yet when

gabapentin is appropriately dosed, it appears to be a safe and effective alternative for the

management of mild to moderate AWS based on prior studies mentioned. These studies

are limited by small sample sizes that excluded patients with seizure disorders, delirium

tremens, use of other illicit substances, and unstable medical illnesses or significant

psychiatric illness. This is different from our study that included patients with a history

of complicated alcohol withdrawal, including those with alcohol withdrawal seizures

and/or alcohol withdrawal delirium. One important factor was that in our evaluation of

the gabapentin protocol, a significant number of patients were found to have received

valproate (36.4%). This is important to underscore: not all patients with a history of

complicated alcohol withdrawal received gabapentin monotherapy. We believe the more

frequent adjunctive use of valproate was prompted by the psychiatry consult service,

acting out of caution given the paucity of available data at the outset of the protocol,

recommending that valproate be considered if the patient had a history of prior seizures,

delirium tremens, or previous brain injury.

 In this small retrospective cohort, no patients receiving the gabapentin protocol

developed seizures, delirium tremens, or required transfer to an ICU setting. In addition

to potentially being a safe option, by day 2 the mean CIWA-Ar score in the gabapentin

group was below the threshold for which a benzodiazepine would be administered in a

symptom-triggered fashion. Future research needs to examine the appropriate length of

gabapentin administration for AWS. In the secondary outcomes, there were similar

lengths of stay between the gabapentin protocol and benzodiazepine groups, but CIWA-

Ar scores between groups had a statistically significant difference on days 2 and 3. This

study is not robust enough to conclude that use of a gabapentin protocol is superior to

benzodiazepines, but does add to the literature evidence that the two strategies may be

similar in mild to moderate AWS.

Fifty-nine patients were discharged with a prescription for gabapentin either to

complete a taper or for planned alcohol maintenance therapy for which there is

supporting literature.(16) Given the design, any benefits from continued gabapentin,

medication adherence, or adverse events were unable to be appreciated. These aspects of

initiating the gabapentin for AWS in the hospital setting through early sobriety and then

as alcohol maintenance treatment is another area that warrants further research as it

relates to improving drinking outcomes and readmission rates.

Including being a retrospective chart review, this evaluation of a gabapentin

protocol for AWS has significant limitations. First, the impact of benzodiazepines prior

to the initiation of a gabapentin protocol may have influenced the absence of serious

AWS related serious events (i.e., seizure, ICU admission). However, the majority of

benzodiazepine exposure in the gabapentin group was during arrival to the emergency
department, likely representing real-world management. Second, 19.5% of patients had a

PAWSS score less than 4; and while this percentage may be less given that a

retrospective assessment of PAWSS could under-calculate scores due to missing data; it

is possible that these patients may not have required any pharmacotherapy treatment for

the management of AWS. This is an important consideration that needs to be further

studied given that numerous studies have demonstrated that symptom-triggered treatment

results in a shorter duration of AWS treatment as well as decreased medication exposure.

Yet while an appropriately dosed fixed regimen of gabapentin could lead to over-

treatment of AWS, it would not be expected to result in similar adverse events as over-

treatment with benzodiazepines (i.e., unwanted sedation or a secondary drug-induced

delirium that can delay discharge). Third, the mean first CIWA-Ar score was 8.5 + 6.3

and the mean greatest CIWA-Ar score in the first 24 hours was 11.8 + 7.1. Logistically,

it is possible that there was a delay in initiation of the gabapentin protocol and delivery of

medication from the pharmacy. This may explain the lower first mean daily dose of

gabapentin but could also represent partial days of hospitalization. We do not have this

data to report as we collected total 24 hour daily dosing. Again, these CIWA-Ar scores

represent moderate AWS and as this study did not specifically evaluate the gabapentin

protocol in patients with severe AWS (i.e. CIWA-Ar score >20), no conclusions can be

made about the safety or effectiveness of this strategy in this population. Patients

directly admitted to an ICU presumably also had severe AWS but were excluded in this

study as there is currently insufficient evidence to support gabapentin use in severe AWS.

The gabapentin protocol would not be appropriate in patients with severe renal

dysfunction, patients with severe liver impairment if adjunctive valproate is considered

imperative, or those who cannot be administered oral medications. Fourth, as psychiatry

consults were not obtained in all cases, the mental status of each patient was not able to

be systematically assessed retrospectively. Finally, potential sources of bias exist.

Excluding all patients who received concomitant benzodiazepines could have removed

those who had more severe AWS (possibly clinicians may have felt the patient required

both medications). It could also be that benzodiazepines were needed after gabapentin

initiation due to poor control of AWS with the gabapentin protocol or that

benzodiazepines alone were the reason for any beneficial effects. Although these patients

were excluded to avoid confounding, it is worth noting that this group consisted of only

eight patients. Another concern is possible selection bias, as clinicians may have

selected patients they thought to be at less risk for serious sequelae of AWS to receive

gabapentin. Our secondary outcomes looking at a matched group who received usual

care with benzodiazepines would refute this notion. In fact, patients receiving gabapentin

had numerically higher PAWSS scores, higher CCI scores, and similar first day CIWA-

Ar scores. It should be noted that the PAWSS has been validated in only limited studies

and more data is needed to clearly determine the role of this scale in the hospital setting.

Additionally, 63.6% of gabapentin protocol patients had a psychiatry consult versus

24.7% in the group receiving usual care with benzodiazepines. This could be used as a

marker of severity given psychiatry consults would likely not be obtained for non-serious

AWS. Interestingly, there were also a significant number of patients given valproate in

the gabapentin protocol group and this may have influenced the absent seizure rate.

While the few studies that have been conducted suggesting possible benefits of valproate

for AWS, in the medically ill there may be possible unwanted sequelae from the drug
such as thrombocytopenia, hyperammonemia, and neurologic toxicities. Unfortunately,

we were not able to systematically assess for adverse events associated with valproate;

but adverse events should be mitigated as valproate dosing rapidly decreases after the

first day. Future studies are needed to confirm valproate’s safety and effectiveness in the

setting of AWS when used in conjunction with gabapentin.

The use of gabapentin for AWS has evolved over the last two years at our

institution, initially being used in select individuals as recommended by the

consultation/liaison psychiatry service. It is now being widely used in non-critically ill

medical patients with AWS. Due to this increasing use, non-psychiatric medical services

requested a more formalized institutional order set within the CPOE system, which in

December 2016 passed all required committee reviews to be added electronically.

Additionally, due to the observed favorable outcomes using the gabapentin protocol, a

randomized prospective study evaluating this modality of treatment is currently underway

at Mayo Clinic, Rochester.

Conclusion

We describe our experience with a gabapentin protocol that was informally

utilized by our consultation/liaison psychiatry service. Subsequent interest by medical

services to use gabapentin for AWS required a formalized protocol that is now active

within our CPOE system. In this small sample, use of a gabapentin protocol was not

associated with the occurrence of seizures or transfer to the ICU. Further research is

needed to confirm the safety of gabapentin for AWS as well as to compare factors, such

as decreased length of stay, adverse drug events, and re-hospitalization when using a
scheduled gabapentin versus a symptom-triggered benzodiazepine management

approach.

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Table 1. Patient Characteristics*

Factor Gabapentin Benzodiazepine

Protocol Group Group
Male (%) 72.7% 72.7%

Length of Stay (days) 5.2 + 9.5 5.03 + 3.7

Age (years) 48.7 + 11.4 48.7 + 11.3

Psychiatry consultation obtained 49, 63.6% 19, 24.7%

(n =, %)

CCI score – Severity and Age 1.79 + 2.2 1.51 + 2

Weight Sum of diseases

Admit ALT (U/L) 83 + 74.8 (n=53) 72.7 + 49.9 (n=51)

Admit AST (U/L) 136.3 + 113.7 (n=55) 108.5 + 78.9 (n=62)

Admit Scr (mg/dL) 0.8 + 0.2 (n=77) 1.3 + 4.2 (n=72)

PAWSS score 4.7 + 1.4 4.07 + 1.4

PAWSS score ≥ 4? (n =, %) 62, 80.5% 51, 66.2%

ICU transfer (n =, %) 0, 0% 3, 3.9%

Benzodiazepine in ED (n =, %) 40, 51.9% 44, 57.1%

ED benzodiazepine dose** (mg) 2.3 + 1.6 mg (n=40) 2.4 + 1.2 mg (n=44)

* mean + standard deviation unless otherwise noted; **in lorazepam equivalents;

abbreviations: ALT = alanine transaminase; AST = aspartate aminotransferase; CCI = Charlson
Comorbidity Index; ED = emergency department; ICU = intensive care unit; PAWSS = Prediction
of Alcohol Withdrawal Severity Scale
Table 2. CIWA-Ar Scores and Medication Exposure*, **

Factor Gabapentin Benzodiazepine

Group Group

CIWA-Ar Max day 1 11.8 + 7.1 10.8 + 6.5

(n=75) (n=73)

CIWA-Ar Max day 2 7.2 + 4.6 9.9 + 6.1

(n=62) (n=77)

CIWA-Ar Max day 3 5.3 + 4.9 8.3 + 6.4

(n=49) (n=58)

CIWA-Ar Max day 4 4.1 + 4.3 9.9 + 7.1

(n=30) (n=34)

CIWA-Ar Max day 5 2.9 + 3.8 7.7 + 5.7

(n=16) (n=24)

CIWA-Ar Max day 6 3.2 + 5.7 6.6 + 5.5

(n=6) (n=17)

Benzodiazepine day 1 4.7 + 5.0 mg 3.8 + 6.5 mg

(n=32)
(n=77)

Benzodiazepine day 2 10.8 +15.0 mg 5.9 + 11 mg

(n=15) (n=77)

Benzodiazepine day 3 n/a 4.3 + 8.7 mg

(n=59)

Benzodiazepine day 4 n/a 5.4 + 10 mg

(n=38)

Benzodiazepine day 5 n/a 1.4 + 2.9 mg

(n=28)

Benzodiazepine day 6 n/a 1.5 + 4.6 mg

(n=21)

Gabapentin protocol day 1 1652+826 mg n/a

Gabapentin protocol day 2 2321+642 mg n/a

Gabapentin protocol day 3 2238+697 mg n/a

Gabapentin protocol day 4 1955+783 mg n/a

Gabapentin protocol day 5 1895 +757 mg n/a

Gabapentin protocol day 6 1662+ 656 mg n/a

Non-AWS gabapentin n/a 10 (13.0%);

Dose: 1240 mg +
758.9 mg

Clonidine 8 (10.4%) 3 (3.9%)

Antipsychotics 9 (11.7%) 4 (5.2%)

Valproate 28 (36.4%) 1 (1.3%)

* mean + standard deviation unless otherwise noted; **benzodiazepines in lorazepam

equivalents; abbreviations: CIWA-Ar = Clinical Institute Withdrawal Assessment for Alcohol–
Revised
Figure 1. A Gabapentin Protocol for the Management of Alcohol Withdrawal

Alcohol Withdrawal (Benzodiazepine Sparing Treatment)

• Orders apply to patients (18 years of age and older) and weighing 50 kg or greater.
• All pre-printed doses are based on normal renal and hepatic function and must be assessed for adjustment against
the individual patient’s renal and hepatic function and for interactions with other medications

ALERT
• Benzodiazepine-sparing treatment for alcohol withdrawal has not been validated for patients with severe,
complicated withdrawal, especially if DT’s are present.
• Do not use gabapentin for patients with severe renal insufficiency (estimated CrCl less than 30) or dialysis or who
are unable to take oral medications.
• Continue CIWA to provide a mechanism for nursing staff to monitor patients and notify the primary service if the
patient’s clinical status changes significantly.
• Do not order lorazepam/chlordiazepoxide contingent upon CIWA scores; CIWA is being used only to monitor the
patient’s progress.
• Consider Psychiatry consultation for hospital inpatients for complicated withdrawal, especially if DTs is present.
• Chemical Dependency consult for appropriate patients.

NURSING ASSESSMENT
Registered Nurse to complete the following assessments every hour until CIWA score is less than 10 for three
consecutive assessments.

• CIWA score, heart rate, temperature, blood pressure, respiratory rate.

• When three consecutive CIWA score assessments are less than 10, the frequency of assessments can be changed
to every 4 hours.
• If the CIWA score is 10 or greater on any 4 hour assessments, the frequency of assessments should return to
every 1 hour.
• CIWA specific monitoring should be continued until this order set is discontinued.
• CIWA specific monitoring should be conducted at the same frequency whether the patient is awake or sleeping.
Registered Nurse should awaken patient to administer CIWA.
• Registered Nurse to notify primary service for the following:
• Vital Sign parameters (specify): default parameters: SBP greater than 160 and/or DBP greater than 100
mmHg, HR greater than 100 bpm.
• Change in mental status or excessive sedation.
• Two consecutive CIWA scores greater than or equal to 10 based on the following three objective CIWA
measures: N&V, Tremor and Paroxysmal Sweats.

MEDICATIONS:
Vitamin and Mineral Supplementation:
• Thiamine (Vitamin B1) 100 mg IV/IM once now. (IV route preferred.). Thiamine (Vitamin B1) 100 mg PO
once daily for 4 days. If unable to take oral Thiamine, give 100 mg IV/IM once daily for 4 additional days.
Multivitamin 1 tablet PO once daily. Folic Acid 1 mg PO once daily.

Withdrawal Prevention and Treatment:

Note: Consider Gabapentin if PAWSS score is 4 or greater. If patient is on maintenance gabapentin, taper down to
usual home dose, then resume.
• Normal Renal Function: (estimated CrCl greater than 60 mL/minute)
o Gabapentin 900 mg PO 3 times a day (06-14-22) for 4 days, then 600 mg PO three times a day for 3
days, then 300 mg PO three times a day for 2 days, then discontinue (9 day taper).
• Moderate Renal Impairment: (estimated CrCl 30 to 60 mL/minute)
o Gabapentin 600 mg PO three times a day for 4 days, then 300 mg PO three times a day for 3 days, then
100 mg PO three times a day for 2 days, then discontinue (9 day taper).
Severe Withdrawal, Prior Brain Injury, Existing Seizure Disorder or History of Withdrawal Seizure:
• Consider addition of divalproex to gabapentin. Do not add divalproex sodium for patients with hepatic
disease or significant hepatic dysfunction.
• Divalproex sodium 750 mg PO twice daily for 1 day, then 500 mg PO twice daily for 5 days, then 250 mg PO
twice daily for 3 days, then discontinue (9 day taper).

Hypertension: (significant increase in systolic blood pressure)

• Clonidine 0.1 mg PO three times a day PRN (prescriber to enter BP parameters).

Acute Agitation/Hallucinations:
RN to contact primary service to assess patient prior to giving:
• Thiothixene 4 mg PO every 8 hours PRN.
• Haloperidol 2 mg IV or IM every 4 hours PRN. (Requires ECG monitoring per guidelines.)
Figure 2. Mean daily maximum CIWA-Ar Scores

14

12 *
10 **
CIWA-Ar Scores

8
***
Gabapentin
6 Protocol Group

4 Benzodiazepine
Group
2

0
Day 1 Day 2 Day 3

*: P = 0.179; **: P = 0.007; ***: P = 0.029

Figure 3. Percent of Patients with a Maximum Daily CIWA-Ar Score Greater than 8

70

60
*
50

40 **
Percent

Gabapentin Protocol Group

30 Benzodiazepine Group

20

10

0
Day 1 Day 2 Day 3

Day 1: gabapentin 61.3% (n=46/75) vs. benzodiazepine 60.27% (n=44/73), P = 0.549

Day 2: gabapentin 33.9% (n=21/62) vs. benzodiazepine 57.1% (n=44/77), *: P = 0.009

Day 3: gabapentin 14.3% (n=7/49) vs. benzodiazepine 41.4% (n=24/58), **: P = 0.039